1. Field of the Invention
The present invention relates to a process for preparing the prodrug of angiotensin converting enzyme (hereinafter referred to as "ACE") inhibitors. More particularly, it relates to a process for preparing N-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride (hereinafter referred to as "NEPA-NCA").
2. Description of the Prior Art
Enalapril Maleate of the following formula (II) ##STR2##
which is a well-known antihypertensive agent due to an excellent ACE inhibitory activity. EP215335 discloses a process for preparing the formula (II) by using the NEPA-NCA of the formula (I) as starting material which undergo condensation reaction with L-proline under the basic condition to obtain the N-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-alanine (hereinafter referred to as "Enalapril"): ##STR3##
After adding maleic acid, an amino acid salt as the formula (II) can thus be obtained.
Using NEPA-NCA to react with the different amino acids in similar condensation reactions can obtain the different ACE inhibitors, for example, Ramipril, Trandolapril, Delapril, Imidapril and Quinapril.multidot.HCl.
The processes for preparing NEPA-NCA of the formula (I) are to react N-[1-(S)-ethyoxy carbonyl-3-phenylpropyl]-L-alanine (hereinafter referred as to "NEPA") of the following formula (III) ##STR4##
with phosgene, diphosgene or triphosgene. Those methods are well known and are disclosed in JP57175152A, U.S. Pat. No. 4,496,541 and EP215335. Although the yield of the above phosgene method is relatively high, it is needed to use toxic phosgene in process. As for the purpose of industrial production, there should be a special design for avoiding from the leakage of phosgene, as critical control point for safety control of hazards. Although diphosgene or triphosgene is liquid or solid form at room temperature, however it produces toxic vapor when be heated. Furthermore, the effluents produced by those processes are also pollutive.
U.S. Pat. No. 5,359,086 discloses a non-phosgene method which using N,N'-carbonyldiimidazole instead of phosgene. However N,N'-carbonyldiimidazole is relatively expensive and needs to use phosgene for recovery.